Direct synthesis of highly substituted furans from acyloins and active methylene compounds catalyzed by bismuth triflate

Article abstract of DOI:10.1246/cl.2011.1103

Bi(OTf)₃ was found to be an effective catalyst for a tandem condensation/cyclization of acyloins and β-diketones or β-keto esters to afford highly substituted furans in good yields.

Full text of DOI:10.1246/cl.2011.1103

doi:10.1246/cl.2011.1103
Published on the web September 23, 2011
1103
Direct Synthesis of Highly Substituted Furans from Acyloins
and Active Methylene Compounds Catalyzed by Bismuth Triflate
Kimihiro Komeyama,* Yuuki Ohama, and Ken Takaki*
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University,
Higashi-Hiroshima, Hiroshima 739-8527
(Received July 25, 2011; CL-110623; E-mail: kkome@hiroshima-u.ac.jp)
Bi(OTf)3 was found to be an effective catalyst for a tandem
condensation/cyclization of acyloins and ¢-diketones or ¢-keto
esters to afford highly substituted furans in good yields.
media (This work). The consecutive reaction eliminates only
H2O as a side product, thus, the protocol would be an ideal
process for the furan synthesis.8
To test the feasibility of such hypothesis, benzoin (1a) was
chosen as a model substrate to react with acetylacetone (2a). To
our delight, the expected condensation/cyclization smoothly
proceeded with 5 mol % of Bi(OTf)3 in toluene in 80 °C for 24 h,
leading to the tetrasubstituted furan 3aa in 99% yield (Entry 1,
Table 1). Other Lewis and Brønsted acids like Cu(OTf)2,
Fe(OTf)3, Sc(OTf)3, Zn(OTf)2, and TfOH were ineffective in
the reaction, resulting in lower or negligible yields of 1a (Entries
2-7). In particular, using Cu(OTf)2, Fe(OTf)3, and TfOH caused
the oxidation of 1a to supply benzil (Entries 2, 3, and 7).9 The
bismuth counter ion was very important for efficient reaction,
that is, BiCl3 and Bi(NO2)3 did not work well (Entries 8 and 9).
Additionally, we confirmed that the present reaction did not
occur without Bi(OTf)3. Solvent effects where also significant;
DCE and MeCN were effective similar to toluene (Entries 10
and 11), but THF resulted in much lower yield of 3aa
(Entry 12), wherein the oxidation mainly proceeded.
Furan skeletons are prevalent in many natural and important
pharmaceutical substances,1 and also widely recognized as
useful intermediates in synthetic organic chemistry.2 To synthe-
size the molecules, numerous methods have been explored;
representative examples are depicted in Scheme 1. Among them,
the oldest and most powerful methods would be (a) Paal-Knorr
and (b) Feist-Bénary synthesis,3 in which 1,4-dione compounds
act as starting substrates or intermediates. (c) The reaction of
activated alkynes using an ammonium ylide is also an effective
route to access the furan skeletons.4 Recently, alternative
procedures, (d) transition-metal-catalyzed cycloisomerization
of alcohols, epoxides, and ketones containing alkyne and allene
moieties, have been demonstrated.5 Unfortunately, in most
cases, the limitation lies in the fact that the requisite starting
materials, especially those having suitable substituents are
somewhat difficult to prepare. Therefore, the development of a
more practical method that can be used for furan synthesis with
fewer limitations is desired.
Optimized conditions in hand, we next examined the scope
of active methylene compounds 2 in this furan synthesis.10
These results are summarized in Table 2. ¢-Keto ester 2b and
amide 2c could also successfully react with 1a to afford the
corresponding furans 3ab and 3ac in good yields (Entries 2
On the other hand, acyloins are readily available substrates
by means of the well-studied condensation reaction of aldehydes
or esters.6 We speculated that the acyloins would be good
electrophiles in a condensation of active methylene compounds
like ¢-diketones and ¢-keto esters to produce the corresponding
1,4-diones.7 The obtained intermediates could sequentially
cyclize to produce highly substituted furans under the same
Table 1. Screening of catalysts in the reaction of 1a with 2aa
O
O
X
R
R1
Yield of
3aa/%b
Conv. of
1a/%b
R3
R3
+
O
R4
b
Entry
Catalyst
Solvent
OH
R2
R4
R1
R1
R1
1
2
3
4
5
6
7
8
9
Bi(OTf)3
Cu(OTf)2
Fe(OTf)3
Sc(OTf)3
Zn(OTf)2
BF3¢OEt2
TfOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
99
24
9
trace
trace
trace
trace
trace
trace
99
99
60
42
17
5
4
71
5
R2
Br
O
a
R2
R3
O
R4
R1
R2
O
R2
O
O
N
c
d
R4
N
R1
R2
R1
R1
R3
R4
+
•
R4
BiCl3
O
R3
This work -2H2O
O
Bi(NO2)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
4
R4
10
11
12
99
99
77
R2
MeCN
THF
76
5
O
OH
+
R1
R3
R4
R2
aAll reactions were carried out using 1a (0.24 mmol), 2a
(0.48 mmol), catalyst (5 mol %), and toluene (2.4 mL). bDeter-
mined by GC with tridecane as an internal standard.
Scheme 1.
Chem. Lett. 2011, 40, 1103-1104
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1104
Table 2. Reaction of 1a and active methylene compounds 2
Entry R4, R5 (2)
Time/h Products
24
Yield/%a
94
1
Me, Me (2a)
2
Me, OEt (2b)
24
23
12
11
10
15
12
89
74
90
84
90
88
91
3b
4
Me, NMe2 (2c)
Ph, OMe (2d)
Scheme 2.
5
Ph, OEt (2e)
method is useful a procedure to synthesize furan derivatives in
term of environmental protection. Further synthetic applications
of this protocol are currently on going.
6
4-ClC6H4, OEt (2f)
4-MeC6H4, OEt (2g)
2-MeC6H4, OEt (2h)
This work was supported by a Grant-in-Aid for Scientific
research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
7
References and Notes
1
a) X.-L. Hou, Z. Yang, H. N. C. Wong, in Progress in Heterocyclic
Chemistry, ed. by G. W. Gribble, J. A. Joule, Pergamon, Oxford, 2003,
Vol. 15, pp. 167-205. b) B. A. Keay, P. W. Dibble, in Comprehensive
Heterocyclic Chemistry II, ed. by A. R. Katritzky, C. W. Rees, E. F. V.
Scriven, Elsevier, Oxford, 1997, Vol. 2, pp. 395-436. doi:10.1016/B978-
008096518-5.00047-2.
8c
aIsolated yield. b20 mol % Bi(OTf)3, reaction temperature:
100 °C. Reaction temperature: 50 °C.
2
3
4
5
B. H. Lipshutz, Chem. Rev. 1986, 86, 795.
c
F. Stauffer, R. Neier, Org. Lett. 2000, 2, 3535, and references therein.
M. Fan, Z. Yan, W. Liu, Y. Liang, J. Org. Chem. 2005, 70, 8204.
a) J. A. Marshall, E. D. Robinson, J. Org. Chem. 1990, 55, 3450. b) M. H.
Suhre, M. Reif, S. F. Kirsch, Org. Lett. 2005, 7, 3925. c) A. Sniady, A.
Durham, M. S. Morreale, K. A. Wheeler, R. Dembinski, Org. Lett. 2007,
9, 1175. d) A. Aponick, C.-Y. Li, J. Malinge, E. F. Marques, Org. Lett.
2009, 11, 4624. e) A. Blanc, K. Tenbrink, J.-M. Weibel, P. Pale, J. Org.
Chem. 2009, 74, 4360. f) C. Praveen, P. Kiruthiga, P. T. Perumal, Synlett
2009, 1990.
a) R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719. b) K. T. Finley, Chem.
Rev. 1964, 64, 573. c) A. Hassner, K. M. L. Rai, in Comprehensive
Organic Synthesis, ed. by B. M. Trost, I. Fleming, Pergamon, Oxford,
1991, Vol. 1, pp. 541-577. doi:10.1016/B978-0-08-052349-1.00017-2.
d) R. Breslow, R. Kim, Tetrahedron Lett. 1994, 35, 699.
a) H. Qin, N. Yamagiwa, S. Matsunaga, M. Shibasaki, Angew. Chem., Int.
Ed. 2007, 46, 409. b) J. Kischel, K. Mertins, D. Michalik, A. Zapf,
M. Beller, Adv. Synth. Catal. 2007, 349, 865. c) M. Rueping, B. J.
Nachtsheim, A. Kuenkel, Org. Lett. 2007, 9, 825. d) M. R. Shushizadeh,
M. Kiany, Chin. Chem. Lett. 2009, 20, 1068.
Similar reactions with malononitrile were reported. See: a) K. Gewald,
Chem. Ber. 1966, 99, 1002. b) M. Kidwai, S. Rastogi, R. Venkataramanan,
Bull. Chem. Soc. Jpn. 2003, 76, 203. c) J. I. Pyo, S. H. Lee, C. S. Cheong,
J. Heterocycl. Chem. 2006, 43, 1129.
and 3). Aryl ¢-keto esters 2d-2h were more reactive. These
reactions completed in reduced time (Entries 4-8). The size of
the ¢-keto ketones and esters 2 has a significant influence on the
reaction. Thus, ¢-keto ester possessing bulkier substituents like
tert-butyl and tert-butoxy groups at the R4 and R5 positions,
respectively, did not give the corresponding furans even at
higher temperature (120 °C) and longer reaction time (96 h),
where all substrates remained quantitatively unchanged.
Next, this methodology was extended to the reaction with
other diaryl acyloins (Scheme 2). para- or ortho-Substituted aryl
acyloins smoothly reacted with active methylene compounds 2a
and 2b, giving rise to the corresponding furans in good yields.
Interestingly, dialkyl acyloin like 1e also participated in the
reaction to afford a furan 3ee. Additionally, this method could
apply to furan synthesis from an unsymmetrical acyloin to
supply 3fa in good yield.
6
7
8
9
a) M. Weiss, M. Appel, J. Am. Chem. Soc. 1948, 70, 3666. b) Y. Ogata,
H. Tezuka, Tetrahedron 1970, 26, 5593. c) W.-Y. Sun, N. Ueyama, A.
Nakamura, Tetrahedron 1993, 49, 1357.
In summary, we have demonstrated a mild and direct
process for synthesis of highly substituted furans from simple
and readily available starting materials using Bi(OTf)3 catalyst.
This reaction releases H2O only as a side product. Therefore, this
10 Supporting Information is available electronically on the CSJ-Journal Web
site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2011, 40, 1103-1104
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/